Leukotrienes are a family of inflammatory lipid mediators that are derived from arachidonic acid (AA) by the action of 5-lipoxygenase (5-LO) and 5-lipoxygenase activating protein (FLAP), which mediate acute and chronic inflammation. Leukotriene B4 (LTB4), the first leukotriene isolated, elicits a variety of inflammatory responses, including leukocyte activation, chemotaxis and degranulation (Samuelsson, 1987; Woo, 2002; Yokimizo, 1997). In addition, overproduction of LTB4 is involved in such inflammation-related ailments as bronchial asthma and rheumatoid arthritis (Chen, 1994; Griffiths, 1995; Turner, 1996). It is known that LTB4 produces its biological effects by binding to its receptors, BLT1 and BLT2 (Yokimizo, 1997; Choi, 2008). Most studies of LTB4 receptors have focused on the high-affinity receptor, BLT1, which is expressed exclusively in inflammatory cells such as leukocytes, and plays a role in inflammatory processes (Yokimizo, 1997). In contrast to BLT1, BLT2 has a low affinity for LTB4 and is expressed in a wide variety of tissues, with highest levels in spleen, leukocytes and ovary (Yokimizo, 1997; Kamohara, 2000). No clear physiological function has yet been identified for BLT2. Recently, BLT2 has been recognized as a downstream component of oncogenic Ras, thereby mediating Ras transformation (Choi, 2008). Consistent with the proposed role of ‘LTB4-BLT2’-cascade as downstream component of Ras signaling, enhanced production of LTB4 has been noted in Rat2-HO6 cells (Yoo, 2004). Interestingly, we also observed some enhanced production of LTB4 in Rat2-BLT2 cells overexpressing BLT2 (Yoo, 2004), suggesting the possibility of crosstalk between LTB4 and BLT2 such that each triggers induction of the other. These findings suggest that the transformed phenotype are elicited by an autocrine or paracrine effect of the high level of LTB4 acting via BLT2 to amplify the LTB4-dependent cascade. In agreement with the proposed function of LTB4 and BLT2 as downstream intermediates in H-RasV12 signaling, Rat2-HO6 cells which express oncogenic H-RasV12 cells had increased levels of cPLA2, 5-LO and FLAP, three proteins involved in the synthesis of LTB4 (Yoo, 2004). In that regard, cPLA2 expression is also upregulated in a number of cancer cell lines, and contributes to induction of the transformed phenotypes (Blaine, 2001; Heasley, 1997). Similarly, 5-LO is upregulated in human pancreatic, breast and prostate cancers (Gupta, 2001; Hennig, 2002; Jiang, 2003; Matsuyama, 2004). In addition, 5-LO and LTB4 receptors are highly expressed in human pancreatic cancers, but not in normal pancreatic duct tissue (Jiang, 2003; Ding, 2005), and the LTB4 receptor BLT1 antagonist LY293111 inhibits the growth and induces apoptosis of human pancreatic cancer cells (Tong, 2002). However, the role of BLT2 in malignant transformation remains to be elucidated.
Based on above background, this invention is to make use of BLT2 inhibitors for (1) inducing apoptosis of cancer cells, (2) suppressing metastatic potential of cancer cells, (3) blocking angiogenesis of cancer cells. Also, this invention include (4) a novel strategy for screeing BLT2 signaling inhibitors by measuring the cell growth of Rat2-BLT2 stable cells. Lastly, this invention includes (5) the novel observation of BLT2 overexpression in various human cancers, which is a critical phenomena in tumorigenesis. Thus, this invention claims any use of strategy targeting against BLT2 overexpression or over-activation as a tool for developing therapeutic composition against human cancer.
Throughout this application, several patents and publications are referenced or cited in parentheses. The disclosure of these patents and publications is incorporated into this application in order to more fully describe this invention and the state of the art to which this invention pertains.